Central regulation of atherosclerosis by testosterone-deficiency
睾酮缺乏对动脉粥样硬化的中枢调节
基本信息
- 批准号:10281872
- 负责人:
- 金额:$ 16.2万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-09-06 至 2025-08-31
- 项目状态:未结题
- 来源:
- 关键词:AblationAddressAndrogen ReceptorAndrogensAnimal ModelAstrocytesAtherosclerosisAttenuatedAutopsyBiochemicalBiologyBody CompositionBrainCardiometabolic DiseaseCardiovascular DiseasesCardiovascular systemCastrationCause of DeathCellsChileChronicDataDevelopmentDisease ProgressionDoctor of PhilosophyDyslipidemiasEducational ActivitiesEndocrinologyEventFatty LiverFellowshipGeneticGliosisGlucose IntoleranceGoalsGonadal Steroid HormonesHeart DiseasesHigh Fat DietHistopathologyHumanHyperlipidemiaHyperphagiaHypogonadismHypothalamic structureIncidenceInflammationInflammatoryInternationalInterventionInvestigationLeukocytosisLinkLipidsLipoproteinsLiverLow Density Lipoprotein ReceptorLow-Density LipoproteinsMagnetic Resonance ImagingMediator of activation proteinMedicineMentorsMetabolicMetabolic DiseasesMetabolic syndromeMetabolismMethodsMicrogliaModelingMonocytosisMusNF-kappa BNeurogliaObesityOperative Surgical ProceduresPathway interactionsPeripheralPharmacologyPlasmaPlayPredispositionPreventionPrevention strategyProgram DevelopmentPropertyProprotein ConvertasesRegulationResearchResearch AssistantResearch PersonnelResourcesRiskRisk FactorsRoleSerumSignal TransductionStrokeSubtilisinsSystemTechnologyTestingTestosteroneTrainingTriglyceridesUnited StatesUniversitiesVery low density lipoproteinWashingtonWeight GainWorkatherosclerosis riskbaseblood glucose regulationcardiometabolic riskcardiometabolismcardiovascular disorder riskcardiovascular risk factorcareer developmentdeprivationdesigner receptors exclusively activated by designer drugsdietaryenergy balanceexcessive weight gainexperimental studyfeedingglial activationhigh riskhormone therapyin vivoliver inflammationmacrophagemalemenmouse modelmultidisciplinarymutantnovelnutritionoverexpressionprofessorresponseskillssystemic inflammatory responsetestosterone replacement therapytoolwestern diet
项目摘要
Project Summary
This proposal delineates a 4-year research career development program focused on brain mechanisms by
which sex steroids protect from atherosclerosis. The candidate is currently a Research Assistant Professor in
the Department of Medicine, Division of Metabolism, Endocrinology and Nutrition at University of Washington
(UW). The proposed experiments and didactic work will provide the candidate with a unique set of multi-
disciplinary skills for him to become an independent investigator in the cardiovascular field. The candidate has
completed a PhD degree in Pharmacology at the University of Chile and two postdoctoral fellowships at OHSU
and UW. The applicant’s combination of expertise in sex steroids biology and CNS regulation of metabolism
uniquely qualify him to conduct these studies. In this proposal, he will address key questions in the field of
cardiovascular disease, the answers to which will increase our understanding of the relationship between
androgen deficiency and elevated cardiometabolic risk. Dr. Dorfman and his mentors (Drs. Karin E. Bornfeldt
and Joshua P. Thaler) have created a specific training plan that takes advantage of the intellectual resources
at the UW to guide him through the proposed educational activities and research. The goal of the current work
is to work in mouse models to identify CNS mechanisms by which hypogonadism increases the incidence of
cardiovascular events. Specifically, he will investigate the role of glial cells (microglia and astrocytes) in
cardiometabolic changes that accelerate the progression of atherosclerosis. The proposal focuses on human
evidence that low levels of circulating androgens promotes cardiometabolic dysregulation, and that
hypothalamic gliosis is associated with lower endogenous testosterone and plasma LDL in men. Furthermore,
the preliminary data identify a dramatic synergistic increase of hypothalamic gliosis when hypogonadism
induced by castration and Western-type diet are combined; in this animal model, early markers of
cardiometabolic risk are also evident including increased liver inflammation and triglyceride content, a shift
toward very low density lipoprotein species, and circulating leukocytosis. These findings support studies
proposed in Specific Aim 1 to use animal models with ablation of microglial or astrocyte inflammation to
determine whether hypothalamic gliosis is required for Western-type diet and androgen deficiency to
synergistically predispose to atherosclerosis. Additionally, the candidate has developed and validated a mouse
model in which microglia and astrocytes can be pharmacologically activated through the use of Designer
Receptors Exclusively Activated by Designer Drugs (DREADD) technology. These models of glial activation
provide a tool to determine whether gliosis is sufficient to increase the risk of CVD as proposed in Aim 2.
项目摘要
该提案描述了一个为期4年的研究职业发展计划,重点是大脑机制,
哪种性类固醇可以防止动脉粥样硬化候选人目前是一个研究助理教授,
华盛顿大学医学系代谢、内分泌和营养学系
(UW)。拟议的实验和教学工作将为候选人提供一套独特的多功能
他的专业技能使他成为心血管领域的独立研究者。这位候选人有
在智利大学获得药理学博士学位,并在OHSU获得两个博士后奖学金
和UW。申请人在性类固醇生物学和CNS代谢调节方面的专业知识相结合
唯一有资格进行这些研究的人在这一建议中,他将讨论以下领域的关键问题:
心血管疾病,这个问题的答案将增加我们对心血管疾病之间关系的理解
雄激素缺乏和心脏代谢风险升高。Dorfman博士和他的导师(Karin E.博恩费尔特
和约书亚P.塞勒)制定了一个具体的培训计划,利用智力资源,
在华盛顿大学指导他通过拟议的教育活动和研究。当前工作的目标
是在小鼠模型中工作,以确定性腺功能减退症增加
心血管事件。具体来说,他将研究神经胶质细胞(小胶质细胞和星形胶质细胞)在
加速动脉粥样硬化进展的心脏代谢变化。该提案侧重于人类
有证据表明,低水平的循环雄激素促进心脏代谢失调,
男性下丘脑神经胶质增生与较低的内源性睾酮和血浆LDL相关。此外,委员会认为,
初步数据表明,当性腺功能减退时,
在该动物模型中,通过阉割和西式饮食诱导的早期标记物
心脏代谢风险也很明显,包括肝脏炎症和甘油三酯含量增加,
非常低密度脂蛋白和循环白细胞增多。这些发现支持了
在具体目标1中提出使用具有小胶质细胞或星形胶质细胞炎症消融的动物模型,
确定下丘脑神经胶质增生是否是西式饮食和雄激素缺乏所必需的,
协同地易患动脉粥样硬化。此外,候选人还开发并验证了一种鼠标
一种模型,其中小胶质细胞和星形胶质细胞可以通过使用设计师被激活
设计药物独家激活受体(DREADD)技术。这些神经胶质激活的模型
提供一种工具来确定胶质增生是否足以增加目标2中提出的CVD风险。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Mauricio D Dorfman其他文献
Mauricio D Dorfman的其他文献
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{{ truncateString('Mauricio D Dorfman', 18)}}的其他基金
Central regulation of atherosclerosis by testosterone-deficiency
睾酮缺乏对动脉粥样硬化的中枢调节
- 批准号:
10482387 - 财政年份:2021
- 资助金额:
$ 16.2万 - 项目类别:
Role of estrogens in hypothalamic inflammation and metabolic regulation.
雌激素在下丘脑炎症和代谢调节中的作用。
- 批准号:
10300979 - 财政年份:2021
- 资助金额:
$ 16.2万 - 项目类别:
Role of estrogens in hypothalamic inflammation and metabolic regulation.
雌激素在下丘脑炎症和代谢调节中的作用。
- 批准号:
10482414 - 财政年份:2021
- 资助金额:
$ 16.2万 - 项目类别:
Role of estrogens in hypothalamic inflammation and metabolic regulation.
雌激素在下丘脑炎症和代谢调节中的作用。
- 批准号:
10669772 - 财政年份:2021
- 资助金额:
$ 16.2万 - 项目类别:
Central regulation of atherosclerosis by testosterone-deficiency
睾酮缺乏对动脉粥样硬化的中枢调节
- 批准号:
10680457 - 财政年份:2021
- 资助金额:
$ 16.2万 - 项目类别:
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